Gs. Hotamisligil et al., IRS-1-MEDIATED INHIBITION OF INSULIN-RECEPTOR TYROSINE KINASE-ACTIVITY IN TNF-ALPHA-INDUCED AND OBESITY-INDUCED INSULIN-RESISTANCE, Science, 271(5249), 1996, pp. 665-668
Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of in
sulin resistance in obesity and diabetes through its ability to decrea
se the tyrosine kinase activity of the insulin receptor (IR). Treatmen
t of cultured murine adipocytes with TNF-alpha was shown to induce ser
ine phosphorylation of insulin receptor substrate 1 (IRS-1) and conver
t IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro.
Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF
-alpha-mediated inhibition of IR signaling, whereas transfected 32D ce
lls that express IRS-1 were very sensitive to this effect of TNF-alpha
. An inhibitory form of IRS-1 was observed in muscle and fat tissues f
rom obese rats. These results indicate that TNF-alpha induces insulin
resistance through an unexpected action of IRS-1 to attenuate insulin
receptor signaling.